Our clinical studies show that melancholic depression is associated with concomitant activation of the principal effectors of the stress response, namely, the CRH and locus ceruleus-norepinephrine (LC-NE) systems, while atypical depression seems associated with pathological inactivation of these neuronal elements. Further evidence of functional linkage between the CRH and LC-NE systems derives from our work showing that NE is a potent stimulus to CRH release and data that the icv administration of CRH markedly and kindling preferentially increases LC glucose utilization. To support a role for CRH in the periodic course of affective illness, we have shown that the limbic convulsant procaine produces dose- dependent activation of pituitar-adrenal function in volunteers and releases CRH from hypothalamic organ culture (an effect inhibited by carbamazepine). Moreover, preliminary data suggest that the icv administration of CRH antisera attenuate electrically- kindled seizures. While Anorexia nervosa and major depression share a common defect in CRH regulation which we postulate contributes to many of their common features, patients with the eating disorders show additional abnormalities in mechanisms subserving hunger and satiety which may confer pathophysiological specificity. Hence, bulimics show a marked decrease in the plasma levels of the anorexogenic peptide cholecystokinin in response to food intake in association with decreased satiety, and increased levels of CSF peptide YY, known to significantly increase hunger. In a primate model of depression, we have shown that adverse maternal-offspring interactions significantly inhibit head circumference, limb length, and weight, and predispose to the development of a depressive-like syndrome in subordinate animals and those subjected to brief isolation. As an adjunct to our previous work showing that the CRH stimulation test is helpful in the differential diagnosis between major depression and Cushing's disease, we now have shown that the CSF/plasma ACTH ratio can distinguish between these illnesses in over 95% of cases. In studies employing a chronically implanted lumbar drain, we have shown neuropeptides are secreted into human CSF in a pulsatile fashion with a circadian variation in pulse frequency and amplitude. Because patients with affective illness often show abnormalities in both thyroid and adrenal axes, we explored the relationship between these axes and showed that experimentally- induced hypothyroidism decreased the synthesis and release of CRH while experimentally-induced hyperthyroidism produced the opposite results.